Abstract
Neuroinflammation is an essential mechanism involved in the pathogenesis of subarachnoid hemorrhage (SAH)-induced brain injury. Recently, Netrin-1 (NTN-1) is well established to exert anti-inflammatory property in non-nervous system diseases through inhibiting infiltration of neutrophil. The present study was designed to investigate the effects of NTN-1 on neuroinflammation, and the potential mechanism in a rat model of SAH. Two hundred and ninety-four male Sprague Dawley rats (weight 280–330 g) were subjected to the endovascular perforation model of SAH. Recombinant human NTN-1 (rh-NTN-1) was administered intravenously. Small interfering RNA (siRNA) of NTN-1 and UNC5B, and a selective PPARγ antagonist bisphenol A diglycidyl ether (BADGE) were applied. Post-SAH evaluations included neurobehavioral function, brain water content, Western blot analysis, and immunohistochemistry. Our results showed that endogenous NTN-1 and its receptor UNC5B level were increased after SAH. Administration of rh-NTN-1 reduced brain edema, ameliorated neurological impairments, and suppressed microglia activation after SAH, which were concomitant with PPARγ activation, inhibition of NFκB, and decrease in TNF-α, IL-6, and ICAM-1, as well as myeloperoxidase (MPO). Knockdown of endogenous NTN-1 increased expression of pro-inflammatory mediators and MPO, and aggravated neuroinflammation and brain edema. Moreover, knockdown of UNC5B using specific siRNA and inhibition of PPARγ with BADGE blocked the protective effects of rh-NTN-1. In conclusion, our findings indicated that exogenous rh-NTN-1 treatment attenuated neuroinflammation and neurological impairments through inhibiting microglia activation after SAH in rats, which is possibly mediated by UNC5B/PPARγ/NFκB signaling pathway. Exogenous NTN-1 may be a novel therapeutic agent to ameliorating early brain injury via its anti-inflammation effect.
Original language | English |
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Pages (from-to) | 190-202 |
Number of pages | 13 |
Journal | Brain, Behavior, and Immunity |
Volume | 69 |
DOIs | |
State | Published - Mar 2018 |
ASJC Scopus Subject Areas
- Immunology
- Endocrine and Autonomic Systems
- Behavioral Neuroscience
Keywords
- Brain edema
- Early brain injury
- Microglia
- Netrin-1
- Neuroinflammation
- Subarachnoid hemorrhage
- Microglia/drug effects
- Neuroprotective Agents/administration & dosage
- PPAR gamma/metabolism
- Rats
- Male
- Rats, Sprague-Dawley
- Signal Transduction/physiology
- Netrin-1/administration & dosage
- Animals
- Receptors, Cell Surface/genetics
- Inflammation/drug therapy
- NF-kappa B/metabolism
- Brain/metabolism
- Subarachnoid Hemorrhage/drug therapy